The hepatic metabolism of genetically diabetic (C57BL/KsJ db/db) and normal (C57BL/KsJ) mice is being studied using isotopic tracer techniques in vivo and liver perfusion and liver cell incubation methods in vitro. Gluconeogenesis from endogenous and exogenous substrates is markedly increased in the db/db mice as early as 5 weeks of age. Tissue metabolite analyses and enzyme assays indicate that increased hapatic fructose diphosphatase activity is a major reason for the enhancement of gluconeogenesis. Lipogenesis from glucose and 3-carbon substrates is also increased in the db/db mice as young as 4 weeks of age. This is attributable to increased hepatic levels of acetyl-CoA carboxylase, malic enzyme, ATP-citrate lyase and pyruvate dehydrogenase. The responses of livers of normal and db/db mice to insulin, glucagon and catecholamines are currently under study. Genetically diabetic mice of the misty strain (C57BL/KsJ-m db/db) are being bred to study early events in the pathogenesis of diabetes in these mice.